Lithium deficiency in Alzheimer’s disease: from cerebral bioenergetic failure to therapeutic intervention

Alzheimer’s disease (AD) is traditionally defined as a proteinopathy marked by amyloid-β plaques and neurofibrillary tangles. Emerging evidence, however, now characterizes AD as a disorder of cerebral bioenergetics stemming from mitochondrial dysfunction. A recent paradigm shift proposes that endogenous lithium deficiency may exacerbate AD. Considering the roles of lithium in bioenergetic regulation, it may serve as a link between the cerebral bioenergetic failure and cognitive impairment in AD. In this review, we outline the multifaceted mechanisms of lithium, including glycogen synthase kinase‑3 inhibition, improved mitochondrial function, reduced neuroinflammation, and enhanced cellular resilience, by which lithium collectively restores cerebral bioenergetics and metabolic homeostasis in AD. Next-generation lithium formulations addressing cerebral bioenergetic failure with therapeutic promise against AD are also discussed. In addition, we further propose a precision framework emphasizing early intervention, biomarker-guided strategies, and rational combination therapies. By targeting cerebral bioenergetic failure, lithium-based strategies may open a new door for the disease-modifying therapy against AD.